The molecular pathogenesis of Y. pestis in relevant animal models has been relatively neglected because of the scarcity of secure BSL-3 facilities and trained personnel. The threat of bioterrorism and the emergence of multiply-antibiotic resistant strains of Y. pestis increases the urgency for a more detailed understanding of the host-pathogen relationship at the molecular level that may lead to the design of improved medical countermeasures and diagnostics. RML is one of the few sites in the world where plague pathogenesis can be comprehensively studied at the molecular level. The objective of this project is to establish mouse and rat models of bubonic plague that incorporate flea-to-rodent transmission to investigate the role of specific Y. pestis virulence factors and to characterize the host response to naturally acquired infection. We established a rat model of bubonic plague and characterized the kinetics, microbiology, and histopathology of bubonic plague in rats following intradermal injection of Y. pestis. We used this model to characterize the gene expression profile of Yersinia pestis in the infected lymph node during bubonic plague, using whole-genome microarray technology. Based on these results, we tested the virulence of specific Y. pestis mutant strains to determine the role of bacterial genes predicted to be important in resistance to oxidative and nitrosative stress, two key effector arms of the host innate immune response. We also used the previously established mouse model to determine the role of the chemokine receptor CCR5, a membrane protein of immune cells, in susceptibility to fleaborne bubonic plague. This study was done at RML in collaboration with Donald Mosier of Scripps, who supplied mice with a specific CCR5 deletion mutation. In addition, we evaluated the efficacy of a new live attenuated vaccine for plague developed by David Pascual at Montana State University. This vaccine trial was done at RML using our mouse model of bubonic plague.